Abstract Significance: Donor tissue shortage remains a critical problem in lung transplantation. Recent advances in tissue engineering have allowed for the possibility of generating bioengineered lungs from decellularized organ scaffolds. These scaffolds, created from the donor?s tissue, become functionalized after recellularization with a patient?s own cells. However, translation of whole-lung decell/recell technology to the clinic has been hampered by the lack of sophisticated tissue growth technologies (e.g. bioreactors) that are capable of providing precise feedback and control of the microenvironment within the scaffold. Innovation: One specific feature that all bioreactors currently lack is a way to noninvasively image the developing organs within them, or quantitatively assess the seeding and growth of cells over time. Currently, these parameters can only be evaluated destructively by histology or by rudimentary input/output assays that have no spatial sensitivity. Therefore, we propose a novel bioreactor that will provide a new layer of information and feedback to the user based on 3D contrast-enhanced ultrasound/photoacoustic (USPA) image data. USPA is a new functional imaging modality that utilizes a light source to generate ultrasonic waves throughout a tissue volume. This approach can provide noninvasive high-resolution images of cellular distribution and cellular metabolism in 3D. Team: SonoVol, Inc., a company specializing in 3D robotic ultrasound imaging, will partner with a team of tissue engineer (UMN), photoacoustics (Johns Hopkins), and medical image analysis (Kitware) experts to build a specialized bioreactor with integrated noninvasive molecular imaging feedback. Hypothesis: The USPA enabled bioreactor will improve whole-organ engineering research by providing real time quantitative feedback on cellular distribution and metabolism. This will accelerate the experimental feedback loop as compared to conventional histology, as well as reduce costs. Approach: During Phase I we will demonstrate feasibility within a mouse lung. During Phase II we will scale the system up for use in translational-sized porcine organs, and perform the commercial R&D necessary to deliver our first calibrated and validated systems to customers. Impact: This technology will be the first commercially available bioreactor of its kind, specifically designed for noninvasive molecular imaging and nondestructive assessment of the 3D organ constructs. Initially its commercial impact will be primarily focused at academic research institutions, however as lung bioengineering technologies mature, the technology could eventually serve a critical role in biotech after bioengineered lungs are approved for clinical use.